Induction of Apoptosis by Lovastatin through Activation of Caspase‐3 and DNase II in Leukaemia HL‐60 Cells

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Abstract
Lovastatin, an HMG‐CoA reductase inhibitor, was found to suppress growth and induce apoptosis in culture human promyelocytic leukaemic cell, HL‐60. However, the mechanisms of lovastatin‐induced apoptosis are still unclear. In this study, we attempted to elucidate the signal transduction pathway for lovastatin‐induced apoptosis in HL‐60 cells in a dose‐ and time‐dependent manner. The features of this apoptosis were attenuated by the presence of mevalonate, a metabolic intermediate of cholesterol synthesis. Treatment of lovastatin caused a rapid release of mitochondrial cytochrome c into cytosol and subsequent induction of caspase‐3, but not caspase‐1 activity. Lovastatin also stimulated proteolytic cleavage of poly‐(ADP‐ribose) polymerase (PARP), and followed by the appearance of caspase activity and DNA fragmentation. Pretreatment with caspase‐3 inhibitors, Ac‐DEVD‐CHO and Z‐VAD‐FMK, inhibited lovastatin–induced caspase‐3 activity and DNA fragmentation. Furthermore, we demonstrated that DNase II was involved in the DNA fragmentation induced by lovastatin. These results suggested that the mechanism of lovastatin induced HL‐60 cells apoptosis through activation of caspase‐3 and DNase II activities.

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